Advisor | Selim, Mustafa I | |
Author | Mohammed Saleem, Yasir Ihsan | |
Date Accessioned | 2019-08-21T18:32:57Z | |
Date Available | 2020-08-01T08:01:53Z | |
Date Created | 2019-08 | |
Date of Issue | 2019-07-10 | |
xmlui.metadata.dc.date.submitted | August 2019 | |
Identifier (URI) | http://hdl.handle.net/10342/7438 | |
Description | Carcinoma of the prostate (CaP) is the most common cancer in men and the second leading cause of cancer-related death in men worldwide. Despite the available treatments for CaP including surgery and Androgen deprivation therapy (ADT), significant number of CaP patients relapse the CaP as the disease becomes hormonal independent. Therefore, it is important to target cell death pathways that function independently of androgen signaling. p53 is a tumor suppressor that mediates apoptosis, cell cycle arrest and DNA repair. The most common negative regulator of p53 is MDM2, which is itself a target gene of p53 to form an autoregulatory negative feedback loop. MDM2 inhibits p53 transcriptional activity through the induction of p53 polyubiquitination and degradation in the proteasome, leading CaP cells to undergo uncontrolled cell growth and cancer progression. Pomegranates, berries, and walnuts contain several bioactive compounds, including the Ellagitannins (ETs). ETs are polyphenolic compounds that are hydrolyzed in the stomach to form Ellagic acid (EA) which is itself metabolized in the gut microbiota to Urolithin A (UA). The purpose of this study was to investigate the influence of EA and UA on the p53-MDM2 signaling pathway in CaP cells. Three models of CaP cell lines were used because each harbor different p53 genotypes: LNCaP (p53+/+), 22RV1(p53-/+) and PC3 (p53-/-). Here we found that, when 22RV1 and LNCaP when treated with EA and UA, the interaction between p53 and MDM2 was disrupted. As a result, both EA and UA caused an increase in p53 protein levels and increased the steady-state concentration of p21, a main downstream target gene of p53 that mediates cell cycle arrest. In addition, EA and UA increased the levels of PUMA and NOXA proteins, both target genes of p53 which confer p53's pro-apoptotic function. Moreover, we confirmed UA inhibits MDM2-mediated polyubiquitination and degradation of p53. Finally, the data show that EA and UA induce apoptosis in PC3 cells (p53-/-), indicating p53 independent role of these compounds. These results suggest that EA and UA may have potential anti-neoplastic activity in CaP cells that may be at least partially attributed to the stabilization and activation of p53. | |
Mimetype | application/pdf | |
Language | en | |
Publisher | East Carolina University | |
Subject | polyphenols | |
Subject | urolithin a | |
Medical Subject Headings | Prostatic Neoplasms | |
Medical Subject Headings | Tumor Suppressor Protein p53 | |
Medical Subject Headings | Ellagic Acid | |
Medical Subject Headings | Heterocyclic Compounds | |
Medical Subject Headings | Proto-Oncogene Proteins c-mdm2 | |
Medical Subject Headings | Male | |
Title | MOLECULAR MECHANISM OF ELLAGIC ACID AND UROLITHIN A IN THE SUPPRESSION OF PROSTATE CANCER BY INFLUENCING THE p53-MDM2 PATHWAY | |
Type | Doctoral Dissertation | |
xmlui.metadata.dc.date.updated | 2019-08-19T17:36:16Z | |
Department | Pharmacology and Toxicology | |
xmlui.metadata.dc.degree.name | Ph.D. | |
xmlui.metadata.dc.degree.level | Doctoral | |
xmlui.metadata.dc.degree.discipline | PHD-Pharmacology - Toxicology | |
xmlui.metadata.dc.degree.grantor | East Carolina University | |
xmlui.metadata.dc.degree.department | Pharmacology and Toxicology | |
xmlui.metadata.dc.access.option | Restricted Campus Access Only | |
xmlui.metadata.dc.embargo.lift | 2020-08-01 | |
xmlui.metadata.dc.type.material | text | |